Prolonged glucagon exposure rewires lipid oxidation and drives diabetic kidney disease progression

作者：Xingfeng Liu, Jingwen Chen, Shengying Gu, Yibing Chen, Ruiping Zhang, Qingce Zang, Tao Li, Hanwen Li, Difei Lu, Shaocong Hou, Lijuan Kong, Qian Jiang, Caiyi Xing, Wenjia Fan, Yanjun Wan, Jiaqi Zhang, Linyuan Zhu, Chunxiao Ma, Qijin Zhao, Hai Yan, Zeper Abliz, Bing Cui, Pingping Li · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-63529-5 · 被引用次数：3 · 研究领域：Diabetes Treatment and Management、Diabetes Management and Research、Pharmacology and Obesity Treatment

Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease. Tubular abnormalities may precede glomerular pathology and indicate functional progression of DKD. Here, we find glucagon injection exacerbates lipid accumulation and renal injury, in addition to causing morphological changes in proximal tubules, podocytes, and mitochondria in the early phase of DKD in mice. However, the specific knockdown or knockout of Gcgr in renal tubular epithelial cells almost completely halts DKD development. In contrast to the effect of short-term glucagon stimulation, long-term glucagon exposure leads to the reversal of glucagon action (glucagon reversal) in proximal tubular epithelial cells (PTECs), which is characterized by reduced energy production and an increase in lipogenesis through Gcgr-PKA-Creb-mTORC1 pathway. Accordingly, anti-GCGR antibody treatment strongly blocks the pathogenesis of DKD induced by both type 2 and type 1 diabetes. Thus, our results highlight a previously unrecognized role of glucagon/Gcgr signaling in PTEC lipogenesis and DKD. Diabetic kidney disease (DKD) is the leading cause of end-stage kidney failure. This study shows that prolonged glucagon exacerbates lipid accumulation, promoting renal injury in early DKD, rather than lipid oxidation. Targeting glucagon signaling significantly inhibits DKD progression.